Optimization and Scale-up of a Pd-Catalyzed Aromatic C−N Bond Formation: A Key Step in the Synthesis of a Novel 5-HT1B Receptor Antagonist
详细信息 查看全文
- 作者：Hans-Jü ; rgen Federsel ; Martin Hedberg ; Fredrik R. Qvarnströ ; m ; Wei Tian
- 刊名：Organic Process Research & Development
- 出版年：2008
- 出版时间：May 2008
- 年：2008
- 卷：12
- 期：3
- 页码：512 - 521
- 全文大小：262K
- 年卷期：v.12,no.3(May 2008)
- ISSN：1520-586X
文摘
Searching for the best synthetic route for a given target molecule is a complex task and, by the same token, a key deliverable from a process R&D department. In this vein the challenge for our group was to identify a sustainable manufacturing process for a chiral compound, AR-A2, to be developed for the treatment of certain neurological disorders. Besides designing a method for assembling the core (R)-2-aminotetralin nucleus, a key feature in the overall synthesis was to provide a robust procedure for creating a new C−N bond between an aromatic ring and a heterocyclic moiety. The methodology employed a Buchwald−Hartwig coupling, and a highly efficient catalytic process was developed using Pd(OAc)2 as precatalyst, with loadings as low as 0.47 mol % (in laboratory trials one order of magnitude lower) together with (R)-BINAP as ligand. Optimizing the reaction conditions allowed a virtually quantitative conversion of the brominated aromatic substrate after heating to 110−115 °C in toluene for 4 h. Telescoping this step with a succeeding catalytic hydrogenation to effect an N-debenzylation, followed by precipitation of the benzoate salt offered an overall yield for the two consecutive steps of 88% at 125-kg batch size, combined with excellent stereochemical product purity of 98% ee.